A major thrust of our research is to define those factors which influence the generation of somatomedin (Sm). Our earliest experiments indicated that growth hormone was the major hormonal determinant of somatomedin in plasma. During the past year we have conducted many experiments with isolated rat livers. We have recognized an error in experimental design which makes some of these earlier reports suspect. In our system normal rat livers release more somatomedin than hypox rat livers over a three hour period. Addition of growth hormone to the perfusion system induces a moderate but significant increase in somatomedin activity of liver perfusates. One of our main objectives during the coming year is to establish the extent that insulin either by itself or in synergism with growth hormone can stimulate somatomedin generation. We are also interested in the possible influence of under- nutrition and over-nutrition in the ability of liver to generate somatomedin. These studies with isolated livers may help us to explain some puzzling clinical situations in which somatomedin concentrations of plasma do not correspond to mean levels of plasma hGH. For example in kwashiorkor (high hGH and low Sm), obesity (low hGH and normal Sm), postoperative patients with craniopharyngioma (low hGH and normal Sm). A second line of research is an attempt to isolate highly purified somatomedin from amniotic fluid. Preliminary observations have confirmed an enriched concentration of Sm. We hope to obtain material in sufficient purity to use for I125 labeling in a radioreceptor assay. Preliminary experiments indicate that material with the same characteristics as plasma Sm exists in amniotic fluid and can be purified by gel giltration and isoelectric focusing.